NM_000527.5(LDLR):c.1208T>C (p.Phe403Ser) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 2, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003283511.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1208T>C (p.Phe403Ser)]

NM_000527.5(LDLR):c.1208T>C (p.Phe403Ser)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1208T>C (p.Phe403Ser)

HGVS:

NC_000019.10:g.11113299T>C
NG_009060.1:g.28919T>C
NM_000527.5:c.1208T>CMANE SELECT
NM_001195798.2:c.1208T>C
NM_001195799.2:c.1085T>C
NM_001195800.2:c.704T>C
NM_001195803.2:c.827T>C
NP_000518.1:p.Phe403Ser
NP_000518.1:p.Phe403Ser
NP_001182727.1:p.Phe403Ser
NP_001182728.1:p.Phe362Ser
NP_001182729.1:p.Phe235Ser
NP_001182732.1:p.Phe276Ser
LRG_274t1:c.1208T>C
LRG_274:g.28919T>C
LRG_274p1:p.Phe403Ser
NC_000019.9:g.11223975T>C
NM_000527.4:c.1208T>C

Protein change:

F235S

Molecular consequence:

NM_000527.5:c.1208T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1208T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1085T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.704T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.827T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Homo sapiens poly(ADP-ribose) polymerase family member 9 (PARP9), transcript var...
Homo sapiens poly(ADP-ribose) polymerase family member 9 (PARP9), transcript variant 26, non-coding RNA
gi|1917120245|ref|NR_170859.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004007171	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28964736, 31746944 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004007171

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 2, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.

Defesche JC, Stefanutti C, Langslet G, Hopkins PN, Seiz W, Baccara-Dinet MT, Hamon SC, Banerjee P, Kastelein JJP.

J Clin Lipidol. 2017 Nov - Dec;11(6):1338-1346.e7. doi: 10.1016/j.jacl.2017.08.016. Epub 2017 Sep 4. Erratum in: J Clin Lipidol. 2020 Sep - Oct;14(5):742. doi: 10.1016/j.jacl.2020.09.010.

PubMed [citation]

PMID:: 28964736

Familial hypercholesterolaemia workshop for leveraging point-of-care testing and personalised medicine in association with the Lipid and Atherosclerosis Society of Southern Africa.

Marais AD, Kotze MJ, Raal FJ, Khine AA, Talmud PJ, Humphries SE.

Cardiovasc J Afr. 2019 Sep/Oct;30(5):297-304. doi: 10.5830/CVJA-2019-055.

PubMed [citation]

PMID:: 31746944
PMCID:: PMC8802372

Details of each submission

From Ambry Genetics, SCV004007171.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.F403S variant (also known as c.1208T>C), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1208. The phenylalanine at codon 403 is replaced by serine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with familial hypercholesterolemia (Defesche JC et al. J Clin Lipidol, 2017 Sep;11:1338-1346.e7; Marais AD et al. Cardiovasc J Afr, 2019;30:297-304; Ambry internal data). Internal structural analysis showed this alteration as moderately destabilizing to the local structure (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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